Natural History Of Primary Biliary Cirrhosis Research Articles

DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis.

BackgroundAlthough the etiology of primary biliary cirrhosis (PBC) remains enigmatic, there are several pieces of data supporting the thesis that a strong genetic predisposition and environmental factors interact to produce a selective loss of tolerance. The striking female predominance of PBC has suggested that this sex predisposition may be secondary to epigenetic alterations on the X chromosome. In the present study, we rigorously defined the X chromosome methylation profile of CD4, CD8, and CD14 cells from 30 PBC patients and 30 controls. Genomic DNA from sorted CD4, CD8, and CD14 subpopulations was isolated, sonicated, and immunoprecipitated for analysis of methylation. All products were hybridized to a custom-tiled four-plex array containing 27,728 CpG islands annotated by UCSC and 22,532 well-characterized RefSeq promoter regions. Furthermore, bisulfite sequencing was then used for validation on a subsequent group of independent samples from PBC patients and controls. Thence, expression levels of selected X-linked genes were evaluated by quantitative real-time PCR with cDNA samples from all subjects.ResultsWe report herein that a total of 20, 15, and 19 distinct gene promoters reflected a significant difference in DNA methylation in CD4+ T, CD8+ T, and CD14+ cells in patients with PBC. Interestingly, there was hypermethylation of FUNDC2 in CD8+ T cells and a striking demethylation of CXCR3 in CD4+ T cells, which inversely correlated with CXCR3 expression levels in CD4+ T cells from early-stage PBC patients.ConclusionsOur data provides a set of genes with epigenetic alteration likely to be indicators of autoimmunity and emphasizes the role of CXCR3 in the natural history of PBC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0098-9) contains supplementary material, which is available to authorized users.

Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a progressive autoimmune disease of the liver. It is the most common cause of chronic intrahepatic cholestatic liver disease in adults. This review addresses the epidemiology, etiology and genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, complications, and prognosis of PBC. Figures show the pathogenesis and natural history of PBC and histologic features of the four stages of PBC. Tables list diagnostic criteria for PBC via the American Association for the Study of Liver Diseases, differential diagnosis for PBC, medications used to treat PBC, secondary therapy for PBC, and follow-up of patients with PBC. This review contains 2 highly rendered figures, 5 tables, and 45 references.

Extrahepatic Autoimmune Conditions Associated with Primary Biliary Cirrhosis

There is a paucity of information on extrahepatic autoimmune (EHA) conditions associated with primary biliary cirrhosis (PBC) and on the impact of EHA conditions on PBC patients' survival. Our goal was to assess the association between PBC and other autoimmune diseases and the impact of EHA conditions on the natural history of PBC. We took advantage of 361 consecutive PBC patients enrolled between 1975 and 2012 (22 males, 339 females; mean follow-up 8 ± 6.9 years). Any associated EHA conditions, PBC histological stage at diagnosis, biochemical data, physiological history, and extrahepatic malignancies developing during the follow-up were recorded. Survival was analyzed by means of Kaplan-Meier curves. Importantly, 221 patients (61.2 %) had at least one EHA conditions: 45 patients (20.4 %) had Hashimoto thyroiditis; 7 (3.2 %) had Graves' thyroiditis; 65 (29.4 %) had Raynaud's phenomenon; 124 (56.1 %) had Sjogren's syndrome; 8 (3.6 %) had systemic lupus erythematosus; 22 (9.9 %) had scleroderma; 22 (9.9 %) had rheumatoid arthritis; 18 (8.1 %) had cutaneous autoimmune diseases; 8 (3.6 %) had vasculitis; 5 (1.4 %) had celiac disease; and 25 (13.1 %) had other EHA conditions. The proportion of patients with associated EHA conditions enrolled during representative periods (1975-1980, 1981-1990, 1991-2000, 2001-2010, 2011-2012) remained stable. No differences emerged between patients with versus without EHA conditions in terms of mean age at PBC diagnosis, antimitochondrial antibody (AMA), or antinuclear antibody (ANA) positivity, histological stage at diagnosis, smoking habits, alcohol consumption, or BMI >25. Multiple logistic regression analysis showed that only female gender was significantly associated with positivity for EHA conditions (OR 4.8; 95 % CI 1.6-13.7, p = 0.004). The mean survival after the diagnosis of PBC was much the same in patients with and without EHA conditions. In conclusion, EHA conditions are often associated with PBC, especially in female patients, but they do not reduce patient survival.

Increased cancer risk in a large population-based cohort of patients with primary biliary cirrhosis: follow-up for up to 36 years.

The natural history of primary biliary cirrhosis (PBC) has so far mainly been studied in tertiary referral centres. The aim of the present investigation was to describe the natural history of PBC in a large population-based cohort in order to identify risk factors for development of malignancies and disease progression. Four independent hospital databases were searched in 44 hospitals in a geographically defined area, after which all medical records were evaluated on site. In addition, PBC registries in the three liver transplant centers were checked for missed referrals from the area of interest. In total, 992 cases fulfilled the inclusion criteria. The median follow-up was 73months (range 0-434). Mortality was similar to the age- and gender matched population (SMR 1.1; 95% CI 0.9-1.4). Male gender, smoking, and elevated bilirubin, decreased albumin, and elevated AST at time of diagnosis, were associated with an increased risk for the combined end point PBC-related death or liver transplantation. In total, 133 (13%) patients developed one or more malignancies (SIR 1.5; 95% CI 1.1-1.9). There was a ninefold increased risk of developing hepatobiliary malignancies (SIR 9.4; 95% CI 3.04-21.8), a fivefold increased risk of developing urinary bladder cancer (SIR 5.0; 95% CI 1.6-11.6), and a 1.8-fold increased risk of developing breast cancer (SIR 1.8; 95% CI 1.08-2.81). PBC is associated with an increased risk of hepatobiliary, bladder and breast cancer. Still, survival-under treatment with ursodeoxycholic acid (UDCA)-was comparable to the general population in this population-based study.

Escherichia coli infection induces autoimmune cholangitis and anti-mitochondrial antibodies in non-obese diabetic (NOD).B6 (Idd10/Idd18) mice.

Several epidemiological studies have demonstrated that patients with primary biliary cirrhosis (PBC) have a higher incidence of urinary tract infections (UTI) and there is significant homology of the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2), between mammals and bacteria. Previous work has demonstrated that non-obese diabetic (NOD).B6 Idd10/Idd18 infected with Novosphingobium aromaticivorans developed liver lesions similar to human PBC. It was postulated that the biliary disease was dependent upon the presence of the unique N. aro glycosphingolipids in activating natural killer T (NK T) cells. To address this issue, we infected NOD.B6 Idd10/Idd18 mice with either Escherichia coli, N. aro or use of a phosphate-buffered saline (PBS) vehicle control and serially followed animals for the appearance of liver pathology and anti-mitochondrial autoantibodies (AMA). Of striking importance, the biliary disease of E. coli-infected mice was more severe than N. Aro-infected mice and the titre of AMA was higher in E. coli-infected mice. Furthermore, the immunopathology did not correlate with the ability of bacterial extracts to produce antigen-dependent activation of NK T cells. Our data suggest that the unique glycosphingolipids of N. aro are not required for the development of autoimmune cholangitis. Importantly, the data highlight the clinical significance of E. coli infection in a genetically susceptible host, and we suggest that the appearance of autoimmune cholangitis is dependent upon molecular mimicry. These data highlight that breach of tolerance to PDC-E2 is probably the first event in the natural history of PBC in genetically susceptible hosts.

The role of natural killer (NK) and NK T cells in the loss of tolerance in murine primary biliary cirrhosis

One of the major obstacles in dissecting the mechanism of pathology in human primary biliary cirrhosis (PBC) has been the absence of animal models. Our laboratory has focused on a model in which mice, following immunization with a xenobiotic chemical mimic of the immunodominant autoepitope of the E2 component of pyruvate dehydrogenase complex (PDC-E2), develop autoimmune cholangitis. In particular, following immunization with 2-octynoic acid (a synthetic chemical mimic of lipoic acid-lysine located within the inner domain of PDC-E2) coupled to bovine serum albumin (BSA), several strains of mice develop typical anti-mitochondrial autoantibodies and portal inflammation. The role of innate immune effector cells, such as natural killer (NK) cells and that NK T cells, was studied in this model based on the hypothesis that early events during immunization play an important role in the breakdown of tolerance. We report herein that, following in-vivo depletion of NK and NK T cells, there is a marked suppression of anti-mitochondrial autoantibodies and cytokine production from autoreactive T cells. However, there was no change in the clinical pathology of portal inflammation compared to controls. These data support the hypothesis that there are probably multiple steps in the natural history of PBC, including a role of NK and NK T cells in initiating the breakdown of tolerance. However, the data suggest that adaptive autoimmune effector mechanisms are required for the progression of clinical disease.

Vitamin D Receptor Polymorphisms Predispose to Primary Biliary Cirrhosis and Severity of the Disease in Polish Population

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver condition characterized by the immune-mediated damage of the intrahepatic bile ducts. Polymorphisms of vitamin D receptor (VDR) are considered to contribute to its pathogenesis however their incidence varies in different populations and their potential association with the course of the disease has not been studied. In this paper we investigated the incidence and correlation of three VDR polymorphisms (BsmI, ApaI or TaqI) with various clinical, biochemical, and serological factors in a homogenous group of 143 Caucasian patients with PBC. Control group comprises 306 DNA samples from umbilical cord blood of healthy newborn children. When compared to controls, we observed a significant dominance of the b allele in the BsmI (OR = 1.69 [1.27–2.24]; P = 0.0003) and t allele in the TaqI (OR = 0.62 [0.47–0.82], P = 0.0001) in patients with PBC. Moreover the BsmI and TaqI polymorphisms were associated with the presence of advanced fibrosis/liver cirrhosis at the diagnosis of PBC. Pairwise linkage disequilibrium (LD) calculations proved that the analyzed SNPs are within an LD block (100% of LDs were D'>0.9). Our study showed, for the first time, that the analyzed polymorphisms of VRD may exert an effect on a natural history of PBC.

SERIAL ANALYSIS OF AUTOANTIBODIES IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS

BACKGROUND / AIMS Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by progressive destruction of small intrahepatic bile ducts, with portal inflammation, leading to fibrosis and cirrhosis. It is a model autoimmune disease characterized by highly specific autoantibodies, strong female predominance and coincidence of other autoimmune conditions. Many efforts are focused on the field of non-invasive markers, in order to allow a more accurate diagnosis and predict disease severity. The characteristic immunological feature of PBC is the presence of antimitochondrial antibodies (AMA), which are detected in more than 90% of patients, even long before the disease is clinically overt. However, in general AMA lack of prognostic value and do not determine clinically different groups of patients while their changes in titers are not related with disease progression. New autoantibodies continue to be characterized, in the hope of defining markers of disease progression and treatment outcome. During the last years, there is an increasing interest about the frequency and significance of antinuclear antibodies (ANA) in PBC. Among these, antibodies against the nuclear pore membrane glycoprotein (anti-gp210) and against the nuclear protein sp100 (anti-sp100) are highly specific for PBC and can be regarded as additional diagnostic markers. In addition, they have been identified as negative prognostic factors. However, the serial changes of these autoantibodies and the correlation with natural history of PBC and response to treatment with ursodeoxycholic acid (UDCA) have not fully assessed. The aim of the present study was to assess the clinical utility of the presence and serial changes in titers of AMA, ANA-PBC-specific (anti-gp210 and anti-sp100) anti-chromatin antibodies. PATIENTS & METHODS One hundred and ten patients with PBC were followed for a mean duration of 39.9±23 months at the outpatient clinic of the Department of Medicine, Larissa Medical School, University of Thessaly, Larissa, Greece. During this period 512 samples were collected and investigated for the presence of AMA IgG/IgA classes, anti-gp210, anti-sp100 and anti-chromatin, by commercial ELISAs. Biochemical, clinical and histological status at initial presentation and during follow-up visits were included. The Mayo risk score was calculated as a prognostic index at each time point. Liver biopsy were classified according to Ludwig’s classification and biochemical response to ursodeoxycholic acid (UDCA) was evaluated according to Pares criteria.

American association for the study of liver diseases endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis

American association for the study of liver diseases endpoints conference: Design and endpoints for clinical trials in primary biliary cirrhosis

Epidemiology and natural history of primary biliary cirrhosis in a Canadian health region: A population-based study

The recent epidemiology and outcomes of primary biliary cirrhosis (PBC) in North America are incompletely described, partly due to difficulties in case ascertainment. In light of their availability, broad coverage, and limited expense, administrative databases may facilitate such investigations. We used population-based administrative data (inpatient, ambulatory care, and physician billing databases) and a validated International Classification of Diseases coding algorithm to describe the epidemiology and natural history of PBC in the Calgary Health Region (population approximately 1.1 million). Between 1996 and 2002, the overall age/sex-adjusted annual incidence of PBC was 30.3 cases per million (48.4 per million in women, 10.4 per million in men). Although the incidence remained stable, the prevalence increased from 100 per million in 1996 to 227 per million in 2002 (P < 0.0005). Among 137 incident cases with a total follow-up of 801 person-years from diagnosis (median 5.8 years), 27 patients (20%) died and six (4.4%) underwent liver transplantation. The estimated 10-year probabilities of survival, liver transplantation, and transplant-free survival were 73% (95% confidence interval [CI] 60%-83%), 6% (95% CI 2.5%-12.6%), and 68% (95% CI 55%-78%), respectively. Survival in PBC patients was significantly lower than that of the age/sex-matched Canadian population (standardized mortality ratio 2.87; 95% CI 1.89-4.17); male sex (hazard ratio [HR] 3.80; 95% CI 1.85-7.82) and an older age at diagnosis (HR per additional year, 1.06; 95% CI 1.03-1.10) were independent predictors of mortality. This population-based study demonstrates that the burden of PBC in Canada is high and growing. Survival of PBC patients is significantly lower than that of the general population, emphasizing the importance of developing new therapies for this condition.

Natural history and prognostic factors of primary biliary cirrhosis in Taiwan: a follow‐up study up to 18 years

The natural history of primary biliary cirrhosis (PBC) has been little studied in Asia. We conducted a Taiwanese cohort study on the natural history of PBC and analysed the prognostic factors. This study enrolled 96 consecutive PBC patients between 1985 and 2006 to evaluate the baseline characteristics and outcomes. There were 74 females and 22 males. Eighty-five were positive for antimitochondrial antibodies in sera, and 11 were negative. The clinical manifestations and prognosis were similar between these two groups. In a median follow-up of 47.5+/-55.8 months, 27 patients died. Multivariate analysis indicated that the independent prognostic factors were serum albumin (P=0.021), creatinine (P=0.033) and ursodeoxycholic acid treatment (P=0.008). Besides, 42 patients developed adverse outcomes. Albumin (P<0.001), bilirubin (P=0.019) and prothrombin time (PT) (P=0.010) were significant factors. Moreover, a Mayo risk score <5, a Model for End-Stage Liver Disease (MELD) score <6, a Child-Pugh stage A and early liver histology were associated with favourable outcomes. Serum albumin, bilirubin and PT were independent prognostic factors of adverse outcomes for Taiwanese PBC patients. Besides, the Mayo risk score, the MELD score, the Child-Pugh stage and liver histology were also validated to predict survival.

Primary biliary cirrhosis in Asians: Less common than in Europeans, but just as depressing

Primary biliary cirrhosis in Asians: Less common than in Europeans, but just as depressing

Geotherapeutics of primary biliary cirrhosis: Bright and sunny around the Mediterranean but still cloudy and foggy in the United Kingdom

Geotherapeutics of primary biliary cirrhosis: Bright and sunny around the Mediterranean but still cloudy and foggy in the United Kingdom

The Natural History of PBC: Has It Changed?

The prognosis and natural history of primary biliary cirrhosis (PBC) have improved significantly during the last few decades. Patients are diagnosed at earlier stages, are more likely to be asymptomatic at diagnosis, and are more likely to receive medical treatment. The survival of asymptomatic patients is longer than the median survival of symptomatic patients. The natural history of PBC has been assessed in the presence of effective therapy, ursodeoxycholic acid (UDCA). Evidence suggests that UDCA delays histological progression in PBC and decreases the risk of development of esophageal varices. Survival of UDCA-treated patients is better than that of untreated patients and also is better than that predicted by the Mayo model. For patients in early stages of PBC, UDCA treatment may normalize survival. However, patients with stage III and IV PBC do not respond as well to UDCA. Therefore, there is a continued need for additional treatment in patients with advanced disease.

The UDCA dosage deficit: a fate shared with CDCA.

Ursodeoxycholic acid (UDCA) is used both as the treatment of choice in many cholestatic syndromes and as complementary therapy in many liver diseases. However, few dose-finding studies exist, and none has evaluated the efficacy and long-term safety of UDCA therapy in primary biliary cirrhosis (PBC). There is an open debate about UDCA's impact on the natural history of PBC, and no universal evidence of benefits on the major endpoint exists. This is perhaps due to a UDCA dosage deficit. Most clinical trials on PBC therapy have used conservative dosages of UDCA similar to those of chenodeoxycholic acid (CDCA) used for dissolution of gallstones. It may be necessary to re-evaluate the dosage of UDCA that provides the most effective treatment.

Persistence of Autoantibodies against Recombinant Mitochondrial and Nuclear Pore Proteins after Orthotopic Liver Transplantation for Primary Biliary Cirrhosis

Primary biliary cirrhosis is an autoimmune disease characterized by high titer autoantibodies predominantly against mitochondrial antigens PDC-E2, BCOADC-E2 and OGDC-E2. Currently orthotopic liver transplant (OLT) is the major form of treatment for end-stage primary biliary cirrhosis (PBC), but it is still unclear whether the autoimmune response continues post-transplantation. In this study we took advantage of a well-defined collection of sera collected serially before and after liver transplantation. We assayed these sera for quantitative and isotype-specific titers of antibodies against a set of recombinant mitochondrial autoantigens. We also studied reactivity to gp210. Serum samples were taken before transplantation and at intervals of 6 months, 1, 2, and 3 years after OLT. Before OLT 24/35 patients were AMA-positive, including seven out of the 35 to PDC-E2 alone, eight to both PDC-E2 and OGDC-E2, six to both PDC-E2 and BCOADC-E2, two to BCOADC-E2 alone and one to OGDC-E2. Following OLT, the frequency of sera that responded to PDC-E2 alone increased from seven to 12/35. Similarly, reactivity to BCOADC-E2 slightly increased from two to four out of 35. However, there was an overall decrease in sera that responded to more than one antigen. Neither Ig isotype nor subclass of the autoimmune response changed following OLT. Findings with gp210 were similar, in that reactivity to gp210 was found in nine out of 35 patients pre-OLT; following OLT the frequency decreased to seven out of 35 patients. Overall, the titers of AMAs decline slightly during the first year post-OLT, but are equivalent to pre-OLT values by 6 months. Moreover, the antibody subclass/ isotype remained unchanged. These data suggest that the removal of a diseased PBC liver has little, if any, impact on the serological characteristics of PBC. Moreover, it provides information regarding the natural history of PBC, particularly on the long latency time for disease development.